Disturbance in the folding capacity of endoplasmic reticulum (ER) prompts a cellular condition known as ER stress. ER stress is induced in neurodegenerative diseases including Alzheimer?s disease (AD). PERK is one of the major ER stress sensor proteins which can be activated by misfolded protein in ER luminal domain to initiate the ER stress. Accumulating evidences have demonstrated that the PERK activation is closely associated with the pathogenesis of AD. PERK activation can lead to overexpression of BACE1, the deposition of amyloid ? (A?) plaques and the phosphorylation of tau protein. Prolonged PERK activation may also cause the neuronal loss by apoptosis. Solid data from AD animal models have shown that depletion or inhibition of PERK may exhibit substantial neuroprotection and reduce the amount of AD-related plaques in the AD brains. However, the existing PERK inhibitors are ATP-analogues and represent high toxicity and low specificity in vivo. Our data support the hypothesis that misfolded proteins can directly interact with PERK to activate the PERK signaling pathway. We propose to identify novel inhibitors of PERK that can block the interactions between PERK luminal domain and the misfolded protein by high throughput screening. These small molecular inhibitors may represent novel treatments for AD by attenuating the ER stress signals. We have determined the complex crystal structure of PERK luminal domain and its peptide substrate, which allows us to optimize the identified inhibitors by use of structure-based drug design.